The objective of this proposal is to characterize the mechanisms and direction (luminal or vascular) of serotonin (5-HT) release from enterochromaffin (EC) cells of the small intestinal mucosa in rabbit, dog and man. Three experimental models will be used to accomplish this goal. The first model is the chambered mucosal sheet model (Ussing chamber). This model will allow the pharmacologic characterization of enterocyte cell receptors for cholinergic, adrenergic, purinergic and peptidergic agents affecting 5-HT release, under conditions of intrinsic neural blockade induced by tetrodotoxin. It will also allow examination of stimulus-secretion coupling, i.e., the intracellular mediators (Ca++, cyclic AMP) that determine 5-HT release. The model will be used to examine the neural regulation of mucosal 5-HT release. Neural pathways will be activated by electrical field stimulation and the neural and mucosal cell receptors that mediate 5-HT release will be examined with selective pharmacological and immunochemical (antisera) antagonists. The second model is the myenteric plexus-longitudinal muscle (MP-LM) of the small intestine mounted in a muscle chamber. This model allows study of 5-HT release exclusively from serotinergic neurons located within the myenteric plexus. The effect of neural stimulation (electrical and pharmacologic ganglionic stimulation) on 5-HT release will be studied. The third model is the isolated vascularly perfused intestine in which release occurs from both neural (myenteric plexus) and mucosal (EC cells) sources. This model should enable us to determine the direction (luminal versus vascular) of 5-HT release under more physiological conditions. This model also permits the study of two possible functional roles of 5-HT in the jejunum, namely stimulation of contractility and of water and electrolyte secretion. Used in conjunction, the three models are expected to yield interactive information about the mechanisms of 5-HT release and the fate of released 5-HT and to better define the role of 5-HT as a regulator of motility and secretion. They will allow us to test the hypothesis that mucosal 5-HT modulates these function by diffusing in sufficient quantity to activate enteric neural and enterocyte 5-HT receptors.